# NM_018451.5(CPAP):c.1933C>T (p.Arg645Cys)

https://sugi.bio/variant/cpap-p-arg645cys

## Summary

**CPAP p.Arg645Cys (c.1933C>T)** is classified **Likely benign** in CPAP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.00834%, amr); Associated with Inborn genetic diseases.

**At a glance:** Likely benign · review: Single submitter · rsID rs541232925 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the CPAP gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CPAP](https://sugi.bio/atlas/gene/CPAP/) |
| Protein change (HGVS p.) | p.Arg645Cys |
| Coding change (HGVS c.) | c.1933C>T |
| MANE Select transcript | [NM_018451](https://www.ncbi.nlm.nih.gov/nuccore/NM_018451) |
| dbSNP | [rs541232925](https://www.ncbi.nlm.nih.gov/snp/rs541232925/) |
| Variant type | single nucleotide variant |
| Location | chr13:24906105-24906105 (GRCh38) |
| ClinVar | [VCV2349094](https://www.ncbi.nlm.nih.gov/clinvar/variation/2349094/) |

**All HGVS expressions:** `NC_000013.10:g.25480243G>A`, `NC_000013.11:g.24906105G>A`, `NG_009165.2:g.21843C>T`, `NG_009165.3:g.40437C>T`, `NM_018451.5:c.1933C>T`, `NR_047594.2:n.2100C>T`, `NR_047595.2:n.2100C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0823)
- REVEL 0.015 (strongly benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.865 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -1.258, GERP -3.44 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.605**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (24,883,180–24,913,025), spanning 29,845 bp. Chi-square p 0.11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,960 in the highest group · 17/1,612,656 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,992 |
| African / African-American | 0.00267% | 37,480 |
| East Asian | 0.00223% | 44,854 |
| European (non-Finnish) | 0.000763% | 131,012 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}


Curated gene–disease validity (ClinGen):

- **microcephaly 6 with or without short stature** — Definitive (AR)

## Protein context {#protein}

Residue **645** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 56.70, 24% of residues very-high.

**6 experimental structure(s)** (PDB): [5EIB](https://www.rcsb.org/structure/5EIB), [5ITZ](https://www.rcsb.org/structure/5ITZ), [7Q1E](https://www.rcsb.org/structure/7Q1E), [7Q1F](https://www.rcsb.org/structure/7Q1F), [7Z0F](https://www.rcsb.org/structure/7Z0F), [7Z0G](https://www.rcsb.org/structure/7Z0G).

## What this gene does {#gene-function}

*Describes the biological roles of CPAP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CPAP's established molecular role includes transcription coactivator activity. p.Arg645Cys falls in the disordered region.


### Pathways affected {#pathways}

CPAP participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |
| [TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain](https://reactome.org/content/detail/R-HSA-6804115) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription coactivator activity, tubulin binding, protein kinase binding, protein domain specific binding, identical protein binding, gamma-tubulin binding.

**Biological process:** centriole replication, astral microtubule nucleation, positive regulation of receptor signaling pathway via JAK-STAT, regulation of centriole replication, positive regulation of centriole replication, microtubule polymerization.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-07 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CPAP variant pages (same residue, condition, or type): [CPAP p.Arg645His](/variant/cpap-p-arg645his), [CPAP p.Ala137Ser](/variant/cpap-p-ala137ser), [CPAP p.Arg535Trp](/variant/cpap-p-arg535trp), [CPAP p.Arg692His](/variant/cpap-p-arg692his), [CPAP p.Arg723Gly](/variant/cpap-p-arg723gly), [CPAP p.Asn1175Ser](/variant/cpap-p-asn1175ser), [CPAP p.Asp730His](/variant/cpap-p-asp730his), [CPAP p.Asp743Gly](/variant/cpap-p-asp743gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2349094). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*